Identifying and Analyzing Genes Linked to Autoimmune Thyroid Diseases

识别和分析与自身免疫性甲状腺疾病相关的基因

• 批准号: 7489874
• 负责人: YARON TOMER
• 金额: $ 31.34万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-25 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7489874
• 关键词: 10q; 12q; 14q; 20q; Age of Onset; Alleles; Antibodies; Antigen-Presenting Cells; Apoptosis; Autoimmunity; B-Lymphocytes; Binding; Biological; Bos taurus; Candidate Disease Gene; Cattle; Caucasians; Caucasoid Race; Cell Line; Cells; Child; Childhood; Chromosome Mapping; Collaborations; Data Set; Dendritic Cells; Development; Disease; Disease model; Disease susceptibility; Etiology; Family; Genes; Genetic; Genetic Transcription; Genetic Variation; Genome Scan; Genotype; Glutamine; Goals; Grant; Graves' Disease; Haplotypes; Hashimoto Disease; Heterogeneity; IgE; Immune; Immune response; Immunogenetics; In Vitro; Individual; Investigational Therapies; Knowledge; Lead; Link; Linkage Disequilibrium; Linkage Disequilibrium Mapping; Logistic Regressions; Lymphocyte antigen; Maps; Modeling; Mus; Pathway interactions; Patients; Play; Population Study; Positioning Attribute; Predisposition; Prevention strategy; Process; Production; Public Health; Regulator Genes; Reporting; Risk; Role; Scanning; Sequence Analysis; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Staging; Subgroup; Susceptibility Gene; TNFRSF5 gene; Testing; Thyroglobulin; Thyroid Gland; Tissues; Transgenic Mice; Translational Research; Translations; Variant; Work; alpha-1,3-mannosylglycoprotein beta-1,4-N-acetylglucosaminyltransferase; autoimmune thyroid disease; base; experience; gene function; gene interaction; genetic linkage analysis; in vivo; monocyte; novel; novel therapeutics; prevent; promoter; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Genetic factors play a major role in the etiology of autoimmune thyroid diseases (AITD), Hashimoto's thyroiditis (HT) & Graves' disease (GD). Our hypothesis is that the etiology of AITD depends on interactions between immune regulatory genes and thyroid specific genes. Our goals are to identify the AITD susceptibility genes and to dissect the mechanisms by which they cause disease. Our findings during the last grant period, which are the starting point for the specific aims of this proposal, included: (1) Identifying novel AITD loci which are specific for subsets of AITD (Italian patients, & childhood AITD); (2) Narrowing down two major replicated AITD loci (12q & 14q), setting the stage for gene-identification; (3) Discovering a new Kozak sequence SNP in the CD40 gene that predisposes to GD by increasing the translational efficiency of CD40. For the next grant period we propose to build on these finding, and our specific aims are: (1) To identify the AITD susceptibility genes in the two subset specific loci by fine mapping in Italian GD patients, linked to a locus on 3q, and childhood AITD, linked to loci on Xp & 10q; the subset-specific AITD genes may represent novel therapeutic targets specific to subgroups of AITD patients; (2) To identify the AITD susceptibility genes in the 2 major replicated loci on 12q & 14q by linkage disequilibrium mapping, haplotype analysis, and gene sequencing. (3) To test the hypothesis that the CD40 Kozak SNP predisposes to GD by inducing over-expression of CD40 on antigen presenting cells (APC's), causing augmented immune responsiveness, as well as increasing CD40 expression on thyrocytes, thereby focusing the immune response to the thyroid. In vitro studies: we will examine the effects of the CD40 SNP genotypes on CD40 expression, signaling, and function in thyrocytes and APC's, in order to dissect the effects of the SNP on CD40 expression & function in these cells. In vivo studies: We are generating transgenic mice over-expressing CD40 in the thyroid. These mice will enable us to test, in vivo, the effects of CD40 over-expression in the thyroid on susceptibility to the induction of an experimental GD model. We will also use these mice to test CD40 blockade as a novel therapy for experimental GD. In summary, the current proposal builds directly on the knowledge gained in the previous grant period. Our approach has already been successful in identifying novel disease-associated genes. Establishing the immunogenetic pathways causing thyroid autoimmunity will lead to a better understanding of the basic etiology of AITD. This could have a major impact on public health, as it may facilitate the development of mechanism-based treatments in autoimmunity, such as CD40 blockade.

描述（由申请人提供）：遗传因素在自身免疫性甲状腺疾病（AITD）、桥本甲状腺炎（HT）和格雷夫斯病（GD）的病因学中起重要作用。我们的假设是 AITD 的病因取决于免疫调节基因和甲状腺特异性基因之间的相互作用。我们的目标是识别 AITD 易感基因并剖析它们引起疾病的机制。我们在上一次拨款期间的发现是本提案具体目标的起点，包括：（1）识别新的 AITD 基因座，这些基因座特定于 AITD 子集（意大利患者和儿童 AITD）； (2) 缩小两个主要复制的AITD位点（12q和14q），为基因鉴定奠定基础； (3)在CD40基因中发现一个新的Kozak序列SNP，该SNP通过提高CD40的翻译效率而诱发GD。对于下一个资助期，我们建议以这些发现为基础，我们的具体目标是：（1）通过精细定位意大利 GD 患者（与 3q 上的基因座相关）和儿童 AITD（与 Xp 和 10q 上的基因座相关），识别两个子集特定基因座中的 AITD 易感基因；亚群特异性 AITD 基因可能代表针对 AITD 患者亚群的新治疗靶点； (2)通过连锁不平衡作图、单倍型分析和基因测序，鉴定12q和14q 2个主要复制位点的AITD易感基因。 (3) 检验以下假设：CD40 Kozak SNP 通过诱导抗原呈递细胞 (APC) 上 CD40 过度表达，导致免疫反应增强，以及甲状腺细胞上 CD40 表达增加，从而将免疫反应集中于甲状腺，从而诱发 GD。体外研究：我们将检查 CD40 SNP 基因型对甲状腺细胞和 APC 中 CD40 表达、信号传导和功能的影响，以剖析 SNP 对这些细胞中 CD40 表达和功能的影响。体内研究：我们正在培育甲状腺中过度表达 CD40 的转基因小鼠。这些小鼠将使我们能够在体内测试甲状腺中 CD40 过度表达对诱导实验性 GD 模型的敏感性的影响。我们还将使用这些小鼠来测试 CD40 阻断作为实验性 GD 的新疗法。总之，当前的提案直接建立在上一个资助期间获得的知识的基础上。我们的方法已经成功地识别了新的疾病相关基因。建立引起甲状腺自身免疫的免疫遗传学途径将有助于更好地了解 AITD 的基本病因。这可能对公共健康产生重大影响，因为它可能促进基于机制的自身免疫治疗的开发，例如 CD40 阻断。